The central goal of this "Center of Excellence for Research on Complementary and Alternative Medicine" application is to investigate the neurobiology of acupuncture. For the healing art of acupuncture to be fully integrated into mainstream medicine, it needs to be examined within the evidence-based framework of the scientific method. To attain this goal, all three projects will investigate the possible brain pathways and circuitries involved in acupuncture. Projects 1 and 3 will study healthy human subjects and patients, while Project 2 will use animal models to complement human neuroimaging data by studying the underlying neurochemical processes. Moreover, Projects 1 and 2 will both use functional MRI (fMRI) to identify and compare the brain activity involved with different classes of acupuncture points and different acupuncture techniques. The focus of these two Projects will be on the limbic network and its rich monoaminergic irmervations. Project 1 will also probe the central neural substrate of deqi, the acupuncture sensation that is related to clinical efficacy, while Project 2 will also use a blood volume contrast agent and modulating ligands in rat and monkey to provide more specific imaging data. In Project 2, extracellular neurotransmitter concentration will be assessed dynamically with in vivo techniques such as microdialysis. Projects 2 and 3 will also use positron emission tomography (PET) to study the role of the opioid peptidergic system in acupuncture on animals and humans, and Projects 3 will specifically compare the role of this neurotransmitter in acupuncture and in placebo analgesia. All three projects will begin to probe the role of the neuromodulator dopamine in the brain's response to acupuncture by exploring the influence of an enzyme that removes dopamine, catechol-O-methyltransferase or the human genetic polymorphism that codes for variants in this enzyme, on the central effects of acupuncture. The Neuroanatomy and Biostatistics Core will provide a common neuroanatomical and statistical framework to be used by all projects to facilitate structure/function inter-paradigm and inter-species analyses. The Administrative Core will provide administrative and clerical infrastructure for the scientific projects and core and orchestrate their utilization of other locally available core resources including the Harvard Genomics Core and the NCRR-sponsored General Clinical Research Center.